The compounds: 4,5,6,7-tetrahydro-7-oxobenzo[]-thien-4-ylurea of formula (I) and 1,2,3,4-tetrahydro-4-oxo1-naphthylurea of formula (II): ##STR6## wherein R' and R" are substituents, such as hydrogen, alkoxy, alkyl and benzyl are useful and valuable animal growth-promoting agents. The compounds of formula (I) are disclosed in the German Offenlegungschrift No. 2,501,788 issued July 7, 1975, and also the subject of an application for United States Patent, Ser. No. 532,449, filed Dec. 13, 1974. Compounds of formula (II) are disclosed in an application for United States Letters Patent, Ser. No. 582,559, filed May 20, 1975. Both the German Offenlegungschrift and the aforementioned applications are incorporated herein by reference. ##STR7## wherein said amides are the racemic mixtures and the optically active isomers thereof, are useful and valuable intermediates for the synthesis of the above urea compounds represented by formulas (I) and (II). In general, the amides of formulas (III) and (IV) are conveniently prepared by oxidation reactions from the corresponding amides of formulas (V) and (VI) as hereinbelow illustrated in the following manner: ##STR8##
To one equivalent of the amide of formula (V) or (VI) are added from 2 to 8 equivalents and, preferably, from 4 to 5 equivalents of an oxidizing agent, such as a ceric salt, chromic acid, sodium bichromate and equivalents thereof, at a temperature between about 0.degree. C. and 100.degree. C. and, preferably, from 20.degree. C. to 60.degree. C., in an inert solvent such as an aqueous solution of acetic acid, acetonitrile, tetrahydrofuran, dioxane, dimethoxyethane and the like, which can be admixed with nitric acid, phosphoric acid, perchloric acid.
Alternatively, the amides can initially be treated with an oxidizing agent such as chromic anhydride in acetic anhydride, followed by hydrolysis. Further the amides (V) and (VI) can also be oxidized with oxygen or with a mixture of oxygen and an inert gas at atmospheric or superatmospheric pressures in the presence of a cobalt catalyst selected from any suitable Co.sup.+2 and Co.sup.+3 salt, in a solvent selected from lower alkanoic acids, aliphatic or cycloaliphatic ketones, lower alcohols, or mixtures thereof, at a temperature range of 20.degree. C. to 150.degree. C., and preferably 25.degree. C. to 120.degree. C.
Each of the above procedures affords desired intermediates [formulas (III) and (IV)] in satisfactory yields. However, the use of metal oxidizing agents is expensive and their recovery from an oxidizing mixture is difficult. Moreover, the use of an oxidant, such as chromic acid in acetic anhydride, can result in the formation of chromyl acetate, a potentially explosive compound. The oxygen/catalyst route also poses a problem, since it employs flammable solvents, some of which (the ketones) may form potentially dangerous peroxides.
Thus, disposal of the effluents, containing the above oxidants, in the environment can have an undesired impact on same, the magnitude of which can not be predicted with any degree of certainty.
It is apparent, therefore, that if a procedure which does not require any oxidation reactions for the preparation of compounds of formulas (III) and (IV) could be devised, such would fulfil a long felt need in the art.
Surprisingly, it has been found that the compounds of the present invention represented by formulae (VII or VIII) are provided which can be converted with ease to the corresponding compounds of formulas (III) and (IV) as hereinbelow graphically illustrated: ##STR9## wherein R.sub.3 and R.sub.4 are each hydrogen or methyl; as well as the racemic mixtures and the optical isomers thereof.
Hydrolysis of the amides of formulas (III) and (IV) yields the corresponding oxo amines of formula (IX) and (X): ##STR10## which, when reacted with urea, metal cyanates, alkyl or aryl isocyanates, carbamoyl halides, yield the afore-said animal growth regulating compounds of formulas (I) and (II).
According to the invention, the 1,3-dithiolane compounds are represented by formula (XI) below: ##STR11## wherein R.sub.1 is a member selected from the group consisting of 2-thienyl and phenyl; R.sub.2 is a member selected from the group consisting of ##STR12## wherein X is chlorine or bromine; R.sub.3 and R.sub.4 are each members selected from the group consisting of hydrogen and methyl; and when R.sub.1 and R.sub.2 are taken together with the carbon atom to which they are attached they represent a bicyclic moiety selected from the group consisting of ##STR13## wherein the carbon atom of said bicyclic moiety marked with an asterisk is also part of the 1,3-dithiolane ring; U is a moiety selected from the group consisting of ##STR14## and when U is ##STR15## said compounds are the racemic mixtures and the optical isomers thereof.
The reaction sequence leading to the compounds (XI) of the present invention is hereinbelow graphically illustrated by flow diagrams, wherein R.sub.1 of formula (XI) hereinabove is either 2-thienyl or phenyl as indicated in Scheme 1 or Scheme 2, respectively. ##STR16##
Advantageously, the 1,3-dithiolanes of formula (XI) can alternatively be prepared by the following reaction sequence: ##STR17##
Thiophene (a) is reacted with succinic anhydride (c) under Friedel-Crafts reaction conditions to afford 4-(2-thienyl)-4-oxobutyric acid (XII). Substitution of benzene (b) in the above reaction affords 4-phenyl-4-oxobutyric acid (XVII). ##STR18## The oxobutyric acids of formulas (XII) and (XVII) obtained in Step 1 above, are reacted with a suitable 1,2-dithiol (d), R.sub.3 and R.sub.4 are each either hydrogen or methyl, in an aromatic solvent such as benzene, toluene or xylene, in the presence of catalytic amounts of p-toluenesulfonic acid at a temperature range of 25.degree. C. to 120.degree. C. and, preferably, from 75.degree. C. to 110.degree. C. while azeotroping the water formed in the reaction. Alternatively, the reaction is conducted in a C.sub.2 -C.sub.5 alkanoic acid, preferably, acetic acid in the presence of an acid catalyst such as boron trifluoride/methanol, boron trifluoride/ether, ZnCl.sub.2 /Na.sub.2 SO.sub.4, HCl/ether, and the like, at the temperature range specified above, to afford 2-(2-thienyl)-1,3-dithiolane-propionic acid (XIII) and 2-phenyl-1,3-dithiolane-2-propionic acid (XVIII), respectively. R.sub.3 and R.sub.4 are as hereinabove defined. ##STR19## The dithiolane propionic acids of formulae (IIIa) and (IIIb) are converted to the corresponding acid chlorides of formulae (XIV) and (XIX) with oxalyl chloride or thionyl chloride (with a small amount of DMF added if desired) in an inert anhydrous solvent selected from the group consisting of benzene, toluene, xylene, chlorobenzene, at a temperature range of about 0.degree. C. to 30.degree. C. and preferably 15.degree. C. to 30.degree. C. ##STR20##
In this reaction step, the acid chlorides of formulae (XIV) and (XIX) are ring closed with stannic chloride in an inert anhydrous solvent such as methylene chloride, ethylene dichloride and the like, at a temperature range of -20.degree. C. to +20 .degree. C. preferably 0.degree. C. to 10.degree. C., to afford spiro[benzo[b]thiophene-7(6H), 2'-[1,3]dithiolan]-4(5H)-one of formula (XV) and spiro[naphthalene-4(3H), 2'-[1,3]dithiolan]-1(2H)-one of formula (XX), respectively, or derivatives thereof wherein R.sub.3 and R.sub.4 are each hydrogen or methyl. ##STR21## Conversion of the oxo compounds of formulae (XV) and (XX) to the corresponding formamides is achieved by heating same with an equimolar or excess amount of formamide-formic acid or ammonium formate-formic acid mixture at a temperature of about 150.degree. C. to 200.degree. C. and preferably 150.degree. C. to 180.degree. C. for a period of time about 3 to 8 hours to afford N-(5,6-dihydrospiro[benzo[b]thiophen-7(6H), 2'-[1,3-dithiolan]-4-yl)formamide of formula (XVI) and N-(2,3-dihydrospiro[naphthalene-4(3H), 2'-[1,3-dithiolan]-4-yl)formamide of formula (XXI), respectively wherein said compounds are the racemic mixtures and the optical isomers thereof.
The removal of the 1,3-dithiolane group and the simultaneous introduction of an oxo group on the same carbon atom in the compounds of formulae (XVI) and (XXI) is readily accomplished by using mercuric halide, such as mercuric chloride/aqueous calcium carbonate in acetonitrile or acetone, at a temperature range of 20.degree. C. to 70.degree. C., preferably 20.degree. C. to 40.degree. C. to afford the compounds of formulae (III) and (IV) as hereinbelow graphically illustrated: ##STR22##
Next, the amides of formulae (III) and (IV) are hydrolyzed with dilute acid or alkali, preferably an acid (e.g. hydrochloric acid) to 4,5,6,7-tetrahydro-7-oxobenzo[b]thiophen-4-amine of formula (IX) and 1,2,3,4-tetrahydro-4-oxo-1-naphthylamine of formula (X), or salts thereof, as hereinbelow graphically illustrated: ##STR23## and wherein said oxoamines are the racemic mixtures and the optical isomers thereof.
Formulas (I) and (II) urea compounds, wherein R' and R" are hydrogen, may be advantageously prepared from the above-identified oxoamines (or acid salts thereof) by reacting said amines with approximately equimolar amounts of sodium or potassium cyanate, however it is generally preferable to employ 5% to 50% excess of the cyanate.
The reaction can be conducted at atmospheric or superatmospheric pressure at a temperature in the range of 0.degree. C. to 100.degree. C., but is preferably conducted at atmospheric pressure at 0.degree. C. to 70.degree. C. in the presence of a solvent selected from water, polar solvents such as C.sub.1 -C.sub.3 alcohols, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, acetone, methyl ethyl ketone and the like, and mixtures thereof; in the pH range of 5 to 7 and preferably at pH 6. The above reaction may be graphically illustrated as follows: ##STR24##
Substituted ureas of formulae (I) or (II) may be advantageously prepared by treating the above-identified amines of formulae (IX) or (X) with an appropriately substituted alkyl isocyanate of formula: R'--NCO or with a carbamoyl halide of formula: ##STR25## halide, wherein R' and R" are as hereinabove defined and halide may be chloro or bromo. The free bases of (IX) or (X) may be employed or acid addition salts thereof, preferably the hydrochloride, in the presence of an acid acceptor. Suitable acid acceptors may be pyridine, triethylamine (or any suitable tertiary amine), alkali metal carbonates such as potassium carbonate and sodium carbonate, strong basic ion-exchange resins, and aqueous alkali. The reaction may be run from about 0.degree. C. to 100.degree. C., and, preferably, at 0.degree. C. to 70.degree. C. until the desired reaction is complete. The isocyanate or carbamoyl halide is generally used in equimolar amounts but it may be used in excess.
Suitable organic solvents for the above reactions include aprotic aromatic solvents such as benzene, toluene and xylene; chlorinated hydrocarbon solvents such as methylene chloride, chloroform and dichloroethane; ethers such as tetrahydrofuran, diethyl ether, dimethoxyethane, diethylene glycol dimethyl ether and dioxane; ketones such as acetone, methyl ethyl ketone, methyl butyl ketone, methyl isobutyl ketone; or mixtures of said solvents. The above reactions may be graphically illustrated as follows: ##STR26## wherein R' and R" are as hereinabove defined.
All of the hereinbefore described preparations of 4,5,6,7-tetrahydro-7-oxobenzo[b]thiophene-, and 1,2,3,4-tetrahydro-4-oxonaphthalene derivatives yield racemic (dl) mixtures. Should the optically active isomers of the above compounds be desired, these may be obtained by the resolution of the racemic (dl) formulae (IX) and (X) compounds, and using the thus obtained optically active isomers in subsequent reactions.
As stated above, formulae (I) and (II) compounds are useful as growth-promoting agents for animals such as poultry, fur-bearing and farm animals, and the use of said compounds for this purpose provides the added advantage of improving feed conversion for said animals. The term "feed conversion" means the ratio of unit weight of feed per unit weight of gain and improvement in feed conversion means increased weight gain from a given unit of feed consumed.
A growth-promoting amount of a formula (I) or a formula (II) compound or an optically active isomers thereof is administered to a host animal in, or with, the animal's feed. Said compound may also be administered as a subcutaneous implant under the skin of said animal or as a parenteral injection. When administered in the feed of said animals, usually about 0.0001% to about 0.08% by weight, and preferably 0.001% to 0.04% by weight of formula (I) or formula (II) urea, is effective for increasing growth rate and improving feed conversion. When administered as a parenteral injection or subcutaneous implant, usually in amounts that will supply about 0.0005 mg to about 0.2 mg, preferably 0.001 mg to 0.1 mg/kg of body weight per day of the active compound, it will produce the desired improvement in weight gain and enhance feed coversion.
The invention is further illustrated by the non-limiting examples set forth below.